Compartmentalized mitochondrial ferroptosis converges with optineurin-mediated mitophagy to impact airway epithelial cell phenotypes and asthma outcomes

Kazuhiro Yamada, Claudette Croix, Donna B. Stolz, Yulia Y. Tyurina, Vladimir A. Tyurin, Laura R. Bradley, Alexander A. Kapralov, Yanhan Deng, Xiuxia Zhou, Qi Wei, Bo Liao, Nobuhiko Fukuda, Mara Sullivan, John Trudeau, Anuradha Ray, Valerian E. Kagan, Jinming Zhao () and Sally E. Wenzel ()
Additional contact information
Kazuhiro Yamada: University of Pittsburgh
Claudette Croix: University of Pittsburgh
Donna B. Stolz: University of Pittsburgh
Yulia Y. Tyurina: University of Pittsburgh
Vladimir A. Tyurin: University of Pittsburgh
Laura R. Bradley: University of Pittsburgh
Alexander A. Kapralov: University of Pittsburgh
Yanhan Deng: University of Pittsburgh
Xiuxia Zhou: University of Pittsburgh
Qi Wei: University of Pittsburgh
Bo Liao: University of Pittsburgh
Nobuhiko Fukuda: University of Pittsburgh
Mara Sullivan: University of Pittsburgh
John Trudeau: University of Pittsburgh
Anuradha Ray: University of Pittsburgh
Valerian E. Kagan: University of Pittsburgh
Jinming Zhao: University of Pittsburgh
Sally E. Wenzel: University of Pittsburgh

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract A stable mitochondrial pool is crucial for healthy cell function and survival. Altered redox biology can adversely affect mitochondria through induction of a variety of cell death and survival pathways, yet the understanding of mitochondria and their dysfunction in primary human cells and in specific disease states, including asthma, is modest. Ferroptosis is traditionally considered an iron dependent, hydroperoxy-phospholipid executed process, which induces cytosolic and mitochondrial damage to drive programmed cell death. However, in this report we identify a lipoxygenase orchestrated, compartmentally-targeted ferroptosis-associated peroxidation process which occurs in a subpopulation of dysfunctional mitochondria, without promoting cell death. Rather, this mitochondrial peroxidation process tightly couples with PTEN-induced kinase (PINK)−1(PINK1)-Parkin-Optineurin mediated mitophagy in an effort to preserve the pool of functional mitochondria and prevent cell death. These combined peroxidation processes lead to altered epithelial cell phenotypes and loss of ciliated cells which associate with worsened asthma severity. Ferroptosis-targeted interventions of this process could preserve healthy mitochondria, reverse cell phenotypic changes and improve disease outcomes.

Date: 2024
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DOI: 10.1038/s41467-024-50222-2

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